Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

Paolo Zanoni, Sumeet A. Khetarpal, Daniel B. Larach, William F. Hancock-Cerutti, John S. Millar, Marina Cuchel, Stephanie DerOhannessian, Anatol Kontush, Praveen Surendran, Danish Saleheen, Stella Trompet, J. Wouter Jukema, Anton De Craen, Panos Deloukas, Naveed Sattar, Ian Ford, Chris Packard, Abdullah Al Shafi Majumder, Dewan S. Alam, Emanuele Di Angelantonio & 29 others Goncalo Abecasis, Rajiv Chowdhury, Jeanette Erdmann, Børge G. Nordestgaard, Sune F. Nielsen, Anne Tybjærg-Hansen, Frikke Schmidt Ruth Frikke Schmidt, Kari Kuulasmaa, Dajiang Liu, Markus Perola, Stefan Blankenberg, Veikko Salomaa, Satu Männistö, Philippe Amouyel, Dominique Arveiler, Jean Ferrieres, Martina Möller-Nurasyid, Marco Ferrario, Frank Kee, Cristen J. Willer, Nilesh Samani, Heribert Schunkert, Adam S. Butterworth, Joanna M.M. Howson, Gina M. Peloso, Nathan O. Stitziel, John Danesh, Sekar Kathiresan, Daniel J. Rader

Research output: Contribution to journalArticle

186 Citations (Scopus)

Abstract

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a lossof-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

Original languageEnglish (US)
Pages (from-to)1166-1171
Number of pages6
JournalScience
Volume351
Issue number6278
DOIs
StatePublished - Mar 11 2016

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Scavenger Receptors
HDL Lipoproteins
HDL Cholesterol
Coronary Disease
Induced Pluripotent Stem Cells
Homozygote
Proline
Knockout Mice
Leucine
Genes
Hepatocytes
Atherosclerosis
Odds Ratio
Phenotype
Lipids
Population

All Science Journal Classification (ASJC) codes

  • General

Cite this

Zanoni, P., Khetarpal, S. A., Larach, D. B., Hancock-Cerutti, W. F., Millar, J. S., Cuchel, M., ... Rader, D. J. (2016). Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science, 351(6278), 1166-1171. https://doi.org/10.1126/science.aad3517
Zanoni, Paolo ; Khetarpal, Sumeet A. ; Larach, Daniel B. ; Hancock-Cerutti, William F. ; Millar, John S. ; Cuchel, Marina ; DerOhannessian, Stephanie ; Kontush, Anatol ; Surendran, Praveen ; Saleheen, Danish ; Trompet, Stella ; Wouter Jukema, J. ; De Craen, Anton ; Deloukas, Panos ; Sattar, Naveed ; Ford, Ian ; Packard, Chris ; Majumder, Abdullah Al Shafi ; Alam, Dewan S. ; Di Angelantonio, Emanuele ; Abecasis, Goncalo ; Chowdhury, Rajiv ; Erdmann, Jeanette ; Nordestgaard, Børge G. ; Nielsen, Sune F. ; Tybjærg-Hansen, Anne ; Ruth Frikke Schmidt, Frikke Schmidt ; Kuulasmaa, Kari ; Liu, Dajiang ; Perola, Markus ; Blankenberg, Stefan ; Salomaa, Veikko ; Männistö, Satu ; Amouyel, Philippe ; Arveiler, Dominique ; Ferrieres, Jean ; Möller-Nurasyid, Martina ; Ferrario, Marco ; Kee, Frank ; Willer, Cristen J. ; Samani, Nilesh ; Schunkert, Heribert ; Butterworth, Adam S. ; Howson, Joanna M.M. ; Peloso, Gina M. ; Stitziel, Nathan O. ; Danesh, John ; Kathiresan, Sekar ; Rader, Daniel J. / Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. In: Science. 2016 ; Vol. 351, No. 6278. pp. 1166-1171.
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abstract = "Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a lossof-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).",
author = "Paolo Zanoni and Khetarpal, {Sumeet A.} and Larach, {Daniel B.} and Hancock-Cerutti, {William F.} and Millar, {John S.} and Marina Cuchel and Stephanie DerOhannessian and Anatol Kontush and Praveen Surendran and Danish Saleheen and Stella Trompet and {Wouter Jukema}, J. and {De Craen}, Anton and Panos Deloukas and Naveed Sattar and Ian Ford and Chris Packard and Majumder, {Abdullah Al Shafi} and Alam, {Dewan S.} and {Di Angelantonio}, Emanuele and Goncalo Abecasis and Rajiv Chowdhury and Jeanette Erdmann and Nordestgaard, {B{\o}rge G.} and Nielsen, {Sune F.} and Anne Tybj{\ae}rg-Hansen and {Ruth Frikke Schmidt}, {Frikke Schmidt} and Kari Kuulasmaa and Dajiang Liu and Markus Perola and Stefan Blankenberg and Veikko Salomaa and Satu M{\"a}nnist{\"o} and Philippe Amouyel and Dominique Arveiler and Jean Ferrieres and Martina M{\"o}ller-Nurasyid and Marco Ferrario and Frank Kee and Willer, {Cristen J.} and Nilesh Samani and Heribert Schunkert and Butterworth, {Adam S.} and Howson, {Joanna M.M.} and Peloso, {Gina M.} and Stitziel, {Nathan O.} and John Danesh and Sekar Kathiresan and Rader, {Daniel J.}",
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Zanoni, P, Khetarpal, SA, Larach, DB, Hancock-Cerutti, WF, Millar, JS, Cuchel, M, DerOhannessian, S, Kontush, A, Surendran, P, Saleheen, D, Trompet, S, Wouter Jukema, J, De Craen, A, Deloukas, P, Sattar, N, Ford, I, Packard, C, Majumder, AAS, Alam, DS, Di Angelantonio, E, Abecasis, G, Chowdhury, R, Erdmann, J, Nordestgaard, BG, Nielsen, SF, Tybjærg-Hansen, A, Ruth Frikke Schmidt, FS, Kuulasmaa, K, Liu, D, Perola, M, Blankenberg, S, Salomaa, V, Männistö, S, Amouyel, P, Arveiler, D, Ferrieres, J, Möller-Nurasyid, M, Ferrario, M, Kee, F, Willer, CJ, Samani, N, Schunkert, H, Butterworth, AS, Howson, JMM, Peloso, GM, Stitziel, NO, Danesh, J, Kathiresan, S & Rader, DJ 2016, 'Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease', Science, vol. 351, no. 6278, pp. 1166-1171. https://doi.org/10.1126/science.aad3517

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. / Zanoni, Paolo; Khetarpal, Sumeet A.; Larach, Daniel B.; Hancock-Cerutti, William F.; Millar, John S.; Cuchel, Marina; DerOhannessian, Stephanie; Kontush, Anatol; Surendran, Praveen; Saleheen, Danish; Trompet, Stella; Wouter Jukema, J.; De Craen, Anton; Deloukas, Panos; Sattar, Naveed; Ford, Ian; Packard, Chris; Majumder, Abdullah Al Shafi; Alam, Dewan S.; Di Angelantonio, Emanuele; Abecasis, Goncalo; Chowdhury, Rajiv; Erdmann, Jeanette; Nordestgaard, Børge G.; Nielsen, Sune F.; Tybjærg-Hansen, Anne; Ruth Frikke Schmidt, Frikke Schmidt; Kuulasmaa, Kari; Liu, Dajiang; Perola, Markus; Blankenberg, Stefan; Salomaa, Veikko; Männistö, Satu; Amouyel, Philippe; Arveiler, Dominique; Ferrieres, Jean; Möller-Nurasyid, Martina; Ferrario, Marco; Kee, Frank; Willer, Cristen J.; Samani, Nilesh; Schunkert, Heribert; Butterworth, Adam S.; Howson, Joanna M.M.; Peloso, Gina M.; Stitziel, Nathan O.; Danesh, John; Kathiresan, Sekar; Rader, Daniel J.

In: Science, Vol. 351, No. 6278, 11.03.2016, p. 1166-1171.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

AU - Zanoni, Paolo

AU - Khetarpal, Sumeet A.

AU - Larach, Daniel B.

AU - Hancock-Cerutti, William F.

AU - Millar, John S.

AU - Cuchel, Marina

AU - DerOhannessian, Stephanie

AU - Kontush, Anatol

AU - Surendran, Praveen

AU - Saleheen, Danish

AU - Trompet, Stella

AU - Wouter Jukema, J.

AU - De Craen, Anton

AU - Deloukas, Panos

AU - Sattar, Naveed

AU - Ford, Ian

AU - Packard, Chris

AU - Majumder, Abdullah Al Shafi

AU - Alam, Dewan S.

AU - Di Angelantonio, Emanuele

AU - Abecasis, Goncalo

AU - Chowdhury, Rajiv

AU - Erdmann, Jeanette

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Tybjærg-Hansen, Anne

AU - Ruth Frikke Schmidt, Frikke Schmidt

AU - Kuulasmaa, Kari

AU - Liu, Dajiang

AU - Perola, Markus

AU - Blankenberg, Stefan

AU - Salomaa, Veikko

AU - Männistö, Satu

AU - Amouyel, Philippe

AU - Arveiler, Dominique

AU - Ferrieres, Jean

AU - Möller-Nurasyid, Martina

AU - Ferrario, Marco

AU - Kee, Frank

AU - Willer, Cristen J.

AU - Samani, Nilesh

AU - Schunkert, Heribert

AU - Butterworth, Adam S.

AU - Howson, Joanna M.M.

AU - Peloso, Gina M.

AU - Stitziel, Nathan O.

AU - Danesh, John

AU - Kathiresan, Sekar

AU - Rader, Daniel J.

PY - 2016/3/11

Y1 - 2016/3/11

N2 - Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a lossof-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

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Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science. 2016 Mar 11;351(6278):1166-1171. https://doi.org/10.1126/science.aad3517